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J. Biol. Chem., Vol. 279, Issue 21, 22039-22046, May 21, 2004

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Extracellular Matrix-induced Cyclooxygenase-2 Regulates Macrophage Proteinase Expression^*

K. M. Faisal Khan, Louise R. Howe¶||, and Domenick J. Falcone**

From the Department of Pathology and Laboratory Medicine, Vascular Biology Center, and ^¶Department of Cell and Developmental Biology, Joan and Sanford I. Weill Medical College, Cornell University, New York, New York 10021 and ^||Strang Cancer Research Laboratory, New York, New York 10021

Chronic inflammatory diseases are characterized by the persistent presence of macrophages and other mononuclear cells, tissue destruction, cell proliferation, and the deposition of extracellular matrix (ECM). The tissue degradation is mediated, in part, by enhanced proteinase expression by macrophages. It has been demonstrated recently that macrophage proteinase expression can be stimulated or inhibited by purified ECM components. However, in an intact ECM the biologically active domains of matrix components may be masked either by tertiary conformation or by complex association with other matrix molecules. In an effort to determine whether a complex ECM produced by vascular smooth muscle cells (SMC) regulates macrophage degradative phenotype, we prepared insoluble SMC matrices and examined their ability to regulate proteinase expression by RAW264.7 and thioglycollate-elicited peritoneal macrophages. Here we demonstrate that macrophage engagement of SMC-ECM triggers PKC-dependent activation of MAPK^erk1/2 leading to increased expression of cyclooxygenase (COX)-2 and prostaglandin (PG) E₂ synthesis. The addition of PGE₂ to macrophage cultures stimulates their expression of both urokinase-type plasminogen activator and MMP-9, and the selective COX-2 inhibitor NS-398 blocks ECM-induced proteinase expression. Moreover, ECM-induced PGE₂ and MMP-9 expression by elicited COX-2^–/– macrophages is markedly reduced when compared with the response of either COX-2^+/– or COX-2^+/+ macrophages. These data clearly demonstrate that SMC-ECM exerts a regulatory role on the degradative phenotype of macrophages via enhanced urokinase-type plasminogen activator and MMP-9 expression, and identify COX-2 as a targetable component of the signaling pathway leading to increased proteinase expression.

Received for publication, November 20, 2003 , and in revised form, March 11, 2004.

^* This work was supported by National Institutes of Health Research Grants R01-HL40819, R01-HL73375 (to D. J. F.), and R01-CA089578 (to Dr. Andrew J. Dannenberg) and the Heritage Affiliate of the American Heart Association Grant-in-aid 0150884T (to D. J. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Dept. of Pathology, Rm. A678, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021. Tel.: 212-746-6491; Fax: 212-746-8789; E-mail: dfalcone{at}med.cornell.edu.

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